Risk factors for developing intra-abdominal abscess following appendicectomy for acute appendicitis: a retrospective cohort study

Background Laparoscopic appendicectomy is commonly performed in Australia for treatment of acute appendicitis. Intra-abdominal abscess (IAA) is a potential complication following appendicectomy for acute appendicitis. Risk factors for developing post-operative IAA remain controversial and poorly defined. Laparoscopic washout may be performed for patients who develop complication(s) including IAA. The aim of this study was to define risk factors for both the development of IAA and identify patients who may require laparoscopic washout following appendicectomy. Methods Data were obtained from 423 patients who underwent laparoscopic appendicectomy over a five-year period (2012–2017). Clinical (fever, haemodynamics, examination findings), biochemical (white cell count, neutrophil count, C-reactive protein, bilirubin, albumin), radiological (CT free fluid), and operative factors (inflammation, suppuration, free-fluid, perforation, histopathology) collected in the pre-, peri-, and post-operative period(s) were analysed. Results 23 (5.4%) patients developed post-operative IAA. Duration of intravenous antibiotics was significantly longer in patients who developed IAA and in those who required laparoscopic washout (p < 0.0001). C-reactive protein (CRP) on admission (p < 0.05) and appendiceal perforation (p = 0.0005) were significantly higher in patients who either developed IAA or needed laparoscopic washout. No clinical or radiological finding predicted either the development of IAA or need for laparoscopic washout. Conclusion Elevated CRP on admission may predict the development of post-operative IAA formation or the need for laparoscopic washout post-appendicectomy. Prolonged post-operative antibiotic use appears independent of the development of IAA as well as the need for laparoscopic washout. These data highlight the need for clear guidelines on peri-operative antibiotic use following appendicectomy.


Introduction
Acute appendicitis is a common abdominal emergency in Australia.The rate of acute appendicitis in developed countries is 90-100 patients per 100,000 inhabitants per year [1].In Australia, laparoscopic appendicectomy has become the standard procedure for managing acute appendicitis in both adult and paediatric populations, with benefits of reduced post-operative pain, fewer overall complications, lower rates of wound infection, shorter hospital stay and decreased recovery time [2,3].Non-operative management of acute appendicitis has been shown to have similar efficacy and safety to surgical management for uncomplicated appendicitis, however it has been associated with longer hospital stay and higher rate of recurrence when compared to laparoscopic appendicectomy [4].
Post-operative intraabdominal abscess (IAA) is a potential complication following laparoscopic appendicectomy with an overall incidence of approximately 2.2% in the adult population [2].Post-operative IAA is associated with significant morbidity, longer hospital stays and double the hospital costs [5].Management of IAA includes antibiotic therapy with or without percutaneous drainage of the abscess, laparoscopic washout and potential re-operation.Prophylactic laparoscopic washout may also play a role in preventing development of IAA [6] as well as managing other complications arising from laparoscopic appendicectomy including a persistent systemic inflammatory response syndrome (SIRS), persistent abdominal pain and peritonism.
The aim of this study was to further define clinical, radiological, biochemical and operative risk factors for both the development of post-operative IAA and for patients who may require laparoscopic washout following appendicectomy.

Methods
This was a retrospective cohort study which included all patients who underwent laparoscopic appendicectomy for acute appendicitis during a five-year period (2012-2017) at Nepean Hospital, Sydney, Australia.Nepean Hospital is a large, tertiary referral hospital within the Nepean Blue Mountain Local Health District which services a population covering 9179km 2 .Data were collected from the Acute Surgical Unit (ASU) database which is prospectively maintained with updates made regularly throughout the day reflecting realtime changes in patient care.Follow up data were collected if the patient developed a complication during the admission or re-presented to the Emergency Department with a post-operative complication following laparoscopic appendicectomy.
Management of acute appendicitis was directed by locally developed hospital guidelines which are based on retrospective local data and in consultation with the infectious diseases department who advised on peri-operative antibiotic administration.All emergency surgical patients with a diagnosis of acute appendicitis over the age of five (5) were admitted and managed by the Acute Surgical Unit; patients younger than five years were transferred to a dedicated Children's hospital for their management.All patients included in this study underwent laparoscopic appendicectomy during their admission once a diagnosis of acute appendicitis had been made.
The following data were collected: (1) demographics (age, sex, American Society of Anesthesiology (ASA) score and Charlson Comorbidity Index (CCI)); (2) clinical variables (vital signs (temperature, respiratory rate, heart rate); (3) symptoms and their duration (nausea, vomiting, anorexia, migratory pain, right iliac fossa (RIF) pain, peritonism).Biochemical parameters were measured both pre-and postoperatively.These included white cell count (WCC), neutrophil count, C-Reactive Protein (CRP), bilirubin and albumin.Vital signs, WCC, and CRP were measured on the day of surgery and post-operative days one, two and three if the patient was still admitted in hospital.Radiological findings (if performed) included computed tomography (CT) periappendiceal changes, peri-appendiceal collection, free fluid and free gas.Peri-operative data including operative findings, surgical approach, appendiceal perforation, complications, time from admission to first antibiotic dose, post-operative antibiotic duration, length of stay, and readmission rate were also obtained.All operative specimens were sent for formal histopathology and correlated to intra-operative findings.
Acute appendicitis was diagnosed using clinical findings, laboratory investigations and radiology (where indicated and/or performed).A CT of the abdomen and pelvis was performed in patients if an alternative diagnosis was felt to be equally or more likely.Some patients transferred to our hospital for management or sent in for admission from the community presented with pre-operative imaging already available.All patients received peri-operative antibiotics once a decision to proceed with surgery had been made.Unless contraindicated, broad spectrum antibiotics to cover gram negative, gram positive and anaerobic bacteria were administered.Laparoscopic washout was not routinely performed during the index laparoscopic appendicectomy.
Post-operative IAA was suspected in patients with postoperative fever, tachycardia, peritonism and/or persistent abdominal pain.In the immediate post-operative period clinical findings were used to make the provisional diagnosis and direct operative management; cross-sectional imaging was used only if an alternate diagnosis was thought to be more likely responsible for the patient's clinical disposition.Patients with clinical suspicion of an IAA diagnosed within 48-hours post-appendicectomy underwent a laparoscopic washout, often confirming a diagnosis of IAA.If the patient represented to the outpatient clinic or emergency department with clinical suspicion for IAA, cross-sectional imaging was first performed to support the diagnosis prior to further management.Subsequent management consisted then of antibiotics with percutaneous drainage (if amenable to percutaneous access) or laparoscopic washout of the abdominal cavity after considering time since index appendicectomy.
Data was used to analyse three patient groups: 1. Post-operative IAA versus no post-operative IAA.
2. Post-operative IAA and laparoscopic washout versus no post-operative IAA and no laparoscopic washout.3. Laparoscopic washout versus no laparoscopic washout.Analysis was performed using GraphPad Prism software.Univariate descriptive analysis was performed on extracted data as required.Continuous variables were reported as a mean and range and categorical variables as a percentage.Differences between groups were measured using the Fisher's exact test for categorical data and unpaired student t-test for continuous data.Significant level was accepted at p < 0.05.
Selection bias was minimised by including all patients who underwent laparoscopic appendicectomy during 2012-2017 with no other eligibility criteria.Information bias was minimised as the Acute Surgical Unit database is comprehensive and prospectively maintained.Due to limited sample size, patients with missing data were not excluded from the study.

Results
Data were obtained from 423 patients.Demographic data and clinical variables are summarised in Table 1.
The patient population was predominantly adult with mean age 36.7 years (SD ± 19.68).The youngest and oldest patient were aged 5 and 85 years respectively.There were 177 female patients (41.84%) and 246 male patients (58.16%).The ASA score was ≥ 2 in 48.13% of patients, correlating to mild systemic disease or above.The CCI was ≥ 3 in 8.75% of patients, correlating to moderate comorbid burden or above.Average time from hospital admission to surgery was 19.4 h (SD ± 46.00) and the average length of stay was 5.3 days (SD ± 2.22).There was an 8.75% readmission rate.Reasons for readmission included feeling generally unwell (2.78%), wound infection (13.89%), abdominal pain with (5.56%) or without fever (63.89%), abdominal pain and fever with outpatient CT finding of IAA (8.33%), vomiting and diarrhoea (5.56%).
Just under half of all patients underwent pre-operative cross-sectional imaging (n = 206; 48.70%); 173 (83.98%) had peri-appendiceal changes, 22 (10.67%) had a periappendiceal collection, 91 (44.17%) had free fluid, 33 (n = 2), and turbid free-fluid (n = 5).Only one patient had a negative post-operative laparoscopy (n = 1; 5.55%).Duration of symptoms pre-operatively was not found to have a significant effect on post-operative complications (see appendices).The quantitative and categorical variables analysed that were statistically significant in at least one comparative group are summarised in Tables 2 and 3, respectively.Please see appendices for full data analysis.

Post-operative IAA vs. No Post-operative IAA
Post-operative IV antibiotic duration (p < 0.0001) was significantly longer in the group that developed post-operative IAA.

Post-operative IAA and Lap Washout vs. No Postoperative IAA and No Lap Washout
Post-operative IV antibiotic duration (p < 0.0001) was significantly longer and initial CRP (i.e., CRP taken on admission) (p = 0.0430) was significantly elevated in the group that developed post-operative IAA and underwent laparoscopic washout.Appendiceal perforation (p = 0.0005) was significant when compared to the group that did not develop post-operative IAA or require laparoscopic washout.Histologically inflamed and gangrenous/perforated appendicitis had no impact on the two groups (see appendix 4).Clinical findings of RIF peritonism and CT free fluid also did not show significant differences between the groups (see appendix 4).

Lap Washout vs. No Lap Washout
Post-operative IV antibiotic duration (p < 0.0001) was longer and appendiceal perforation (p = 0.0046) more common in the group that received laparoscopic washout.
(16.02%) had free gas and 83 (40.29%) had faecolith visible on imaging.Further data on pre-, peri-and post-operative clinical and biochemical risk factors are provided in the appendices.
All patients received post-operative intravenous antibiotics for an average length of 4.3 days (SD ± 1.78).One quarter of patients (n = 104; 24.59%) received post-operative oral antibiotics; average length of administration was 6.2 days (SD ± 2.69).
Intra-abdominal abscess (IAA) was a complication in 23 patients (5.44%).Over half of these patients were re-admitted following discharge (n = 13; 56.52%).The reasons for re-presentation to hospital were most commonly abdominal pain (69.23%) and abdominal pain with fever (15.38%).A small number had undergone outpatient cross-sectional imaging suggesting a post-operative abscess (15.38%).Of the 23 patients who developed post-operative IAA, 11 (47.83%)patients were diagnosed using clinical findings alone and 12 (52.17%)had an inpatient CT to aid diagnosis.Eighteen patients underwent laparoscopic washout for management.Six (n = 6, 38.89%) of these patients were found to have a post-operative IAA; the remaining patients were found to have a small bowel ileus (n = 2), small bowel obstruction (n = 1), RIF haematoma (n = 1), fibrin deposition in both uncomplicated and complicated appendicitis does not alter the incidence of IAA, however in patients with complicated appendicitis, cessation of intravenous antibiotics in the presence of leukocytosis and fever results in an increased incidence of IAA even if oral antibiotics have been commenced [16].In summary, while post-operative antibiotics may be of benefit, the optimal duration of treatment has yet to be clearly defined although if ceased in the presence of persistent clinical features of a systemic inflammatory response this is likely to result in an intra-abdominal abscess.
The intra-operative pathological findings (as determined by the operating surgeon) frequently determine subsequent clinical management and overall length of hospital stay.In this study, average length of hospital stay was 5.3 days.The possible discrepancy between the qualitative and histopathological findings of the appendix, which are received two weeks post-operatively, raise the possibility patients are potentially either over-or undertreated.In this study operative records were not reviewed.Future studies are underway in order to correlate intra-operative descriptors used to guide management with histopathological results in order to optimise patient care and hospital spending.
Interestingly, the clinical findings of RIF peritonism and free fluid on cross-sectional imaging did not help differentiate between patients that developed post-operative IAA and those that did not.This finding suggests there is a limitation in both clinical examination and radiological investigations when used in the post-operative setting to determine which patients have (or are developing) IAA.
Non-operative management of acute appendicitis has been discussed in the literature, particularly for management in paediatric populations.Research has shown a promising role for non-operative management in uncomplicated, early, acute appendicitis, suggesting it is feasible, safe, cost effective and more favourable among parents and patients [17,18].A review by Wilms et al. suggests non-operative management of uncomplicated acute appendicitis in all age groups is associated with fewer complications but may be less efficacious than surgical management [19].In nonoperative management, criteria for determining suitable patients have yet to be developed.The identification of suitable patients for non-operative management has previously relied on CT imaging which is difficult and contentious in the paediatric population, due to the risks associated with radiation exposure.Our results identify a role for CRP as a predictor of the success of non-operative management, mitigating the use of imaging.Further studies with larger patient cohorts are required to better characterise CRP levels in acute appendicitis and its potential clinical role.
We acknowledge there are several limitations to the present study.Although a retrospective analysis we thoroughly

Discussion
The results of the present study are three-fold.Firstly, they identify a novel use for CRP as a biochemical marker in the context of identifying those patients at greater risk of developing post-operative IAA.Secondly, these results suggest the development of post-operative IAA and need for laparoscopic washout occurs despite prolonged use of IV antibiotics following appendicectomy.Lastly, these results highlight the complex nature of acute appendicitis particularly with respect to factors influencing the development of post-operative IAA.
The identification of CRP on admission as a pre-operative predictor for patients who are likely to develop postoperative IAA and need laparoscopic washout is of clinical significance, as this suggests a role for minimally invasive pre-operative testing in predicting clinical prognosis and directing course of management.To the best of our knowledge, CRP has not previously been implicated as a risk factor for developing post-operative IAA, however its role in other acute disease states is well characterised.For example, CRP levels are used as a criterion to rule out, with a high probability, the presence of necrosis in acute pancreatitis [13].
The results of the present study suggest that development of post-operative IAA and need for laparoscopic washout is independent of post-operative IV antibiotic duration, as those who developed post-operative IAA and received laparoscopic washout had a significantly longer course of post-operative IV antibiotics.Currently, in Australia, postoperative antibiotic use is determined by hospital-dependent policies and can depend on other factors, including the preference of the operating surgeon and presence of clear instructions for post-operative antibiotics.At our institution, patients with gangrenous or perforated appendicitis receive IV antibiotics for 5 days regardless of clinical progress, and patients with suppurative appendicitis receive IV antibiotics for 2 days, as a preventative measure against developing post-operative IAA and needing laparoscopic washout.However, our data suggests these patients developed an abscess requiring laparoscopic washout despite a longer duration of antibiotics.
Kimbrell et al. have shown previously there is no difference in the rate of developing post-operative IAA when antibiotics are ceased 24 h post-operatively as compared to patients in whom they are continued for more than 24 h [14].A systematic review on postoperative antibiotic use in adults with acute appendicitis recommends a course of broad-spectrum IV antibiotics for 3-5 days in cases of appendiceal perforation, however no recommendation is made as to when antibiotic cessation is appropriate.[15].Further data has shown that prolonging antibiotic therapy

Table 1
Patient demographics and pre-, peri-and post-operative factors ASA American Society of Anesthesiologists; CCI Charlson Comorbidity Index; CT Computed tomography

Table 2
Analysis of significant quantitative variables across all three comparative groups

Table 3
Analysis of significant categorical variables across all three comparative groups Post-op IAA vs.